Alzheimer's disease (AD) is the most common cause of dementia in the elderly. The characteristic hallmark of AD is characterized by the presence of amyloid plaques, composed A2 peptide, and tangles composed of hyperphosporylated tau. ApoE (Apolipoprotein E), a cholesterol carrier in the brain is the only known and most widely accepted genetic risk factor for late onset AD (Onset before age d65). Genetic variation in the APOE gene has been associated with late-onset of AD. In humans, APOE has three polymorphic alleles: E2, E3, and E4 which differ from each other by one amino acid. APOE4 is associated with increased odds of early onset of AD (onset before age 65) and accounts for up to 40-50% of genetic risk of AD. ApoE binds to cell surface receptors like ApoER2, to transport cholesterol and other essential lipids to the neurons. ApoER2 is predominantly expressed in the brain and is involved in neuronal migration, cortical lamination, and synapse function. Interestingly, apoE receptors undergo proteolytic cleavage by -secretase like APP, releasing intracellular domains that interact with common adaptor proteins. ApoER2 binds extracellular ligands like Reelin, and intracellular ligands like Fe65, X11, Dab1, affecting in its trafficking and /or signaling. These modifications are crucial for neuronal migration, dendritic spine development, and synaptic plasticity. Over the past few years, a large amount of evidence shows that ApoE receptors directly or indirectly alter expression, distribution and trafficking of APP, thereby altering APP processing and A2 production. APP and ApoER2 interact via intra and extracellular ligands, binding of which can alter APP processing and A2 production. The goal of this proposal is to determine if ApoER2 competes or associates with APP for adaptor proteins and if apoE isoforms differentially regulate this interaction to alter APP processing and A2 production and if apoE isoforms alter the interaction between ApoER2 and APP in vitro and in vivo to alter A2 production. This study will help define the function of apoE in the CNS, and identify a novel mechanism by which ApoE alters A2 production in vivo. If ApoER2 alters APP metabolism in an ApoE isoform dependent mechanism, ApoER2 can be a putative drug target PUBLIC HEALTH RELEVANCE: Neurodegenerative like Alzheimer's disease cause an immense burden on society both psychologically and financially. The goal of this project is to identify the mechanism by which apoE, the only know risk factor regulates APP metabolism and A2 generation. The research in this proposal seeks a deeper understanding of the mechanisms that underlie the advancement of the diseases with the hope that this understanding may one day lead to their prevention or slowed progression.